Preparation of new therapeutically useful heterocyclic compounds



Patented July 11, 1944 PREPARATION OF NEW THERAPEUTICALLY USEFUL HETEBOCYCLIO COMPOUNDS 1 Arthur James Ewins', Gidea Park, Romford, and

Montague Alexander Phillips, Romford, England, assignors to May & Baker, Limited, Lon- I i don. England, a company of Great Northern Ireland Britain and No Drawing. Original application November 1,"

1938, Serial No. 238,164. Divided and this application April 19, 1940, Serial No. 330,526 in Great Britain, India, Australia, and New Zealand November 29, 1937 1 Claim. (01. act-239.6)

This is a division of co-pending application Serial No. 238,164, filed November 1, 1938, for The preparation of new therapeutically useful heterocyclic compounds.

The present invention relates to the preparation of p-amino-benzene-sulphonamido derivatives of the pyridine, quinoline and isoquinoline series, many of which have marked bactericidal properties and are capable of therapeutic application.

The compounds prepared acording to the present invention are of the type in which R represents a heterocyclic nucleus of the pyridine, quinoline or isoquinoline series and in which R1 may be hydrogen, acyl, alkyl, aryl or aralkyl, and R2 may be hydrogen or alkyl and R3 may be hydrogen, alkyl, aryl, aralkyl or acyl.

According to the present invention these compounds may be prepared by various methods which may be summarised as follows:

A. Derivatives in which RIRZ and R3 are hydrogen atoms may be prepared by condensing a compound of the type p-X CsI-I4Y with a compound of the type ZR in which R is a pyridine, quinoline or isoquinoline residue, and when Y is SOzCl, X is NHz and when Y is SOaNHz Z is a halogen, to form compounds of the type -X C6H4sO2NHR which can be ,readily converted into compounds of the type NHzCaI-I4SO2NHR. X therefore represents a group such as an acylamino group, a nitro group, an em group linked to an organic radicle, or a halogen, which groups may be converted into an amino group by hydrolysis in the first mentioned case, by reduction in the secondand third mentioned cases, or by the action of ammonia in the fourth case.

B. Similarly, derivatives in which R1 and R2 are hydrogen atoms, and R3 an aryl, alkyl, or aralkyl group may be prepared by condensation of compounds of the type p-XC6H4Y with compounds of the type ZR in which when Y is SOzCl, Z is NHRs and when Y is SOzNI-IRs, Z is a halogen to form compounds of the type p-XCGH4SO2NR3R from which, the required amino products may be obtained as described inparagraph A.

C. Derivatives in which R1 is hydrogen or an alkyl or acyl group, R2 is an ,alkyl, aryl, or ara'lkyl group and R3 is either hydrogen or analkyl, aryl,

or aralkyl group may be prepared by condensing a compound of the type R1RzN.C'6H4Y with a compound of the type ZR in which R is the residue of l a pyridine, quinoline or.i'soquinoline base and when Y is SOzCl, Z is NHRa and when Yis SO2NHR3, Z is ahalogene I v D. Derivatives in which. R; is a hydrogen or alkyl, R2 is an alkyl, and- Bs is hydrogen or, an alkyl, aryl or aralkyl group. may be prepared from condensation products of the types def-c scribed in A and B in which X'is 'a halogenby reacting on the respective'halogenated conden sation products with a" primary or secondary amine instead of with ammonia.

E. Acyl, alkyl, aryl or aralkyl derivatives .01? compounds prepared by the foregoing methods containing one or more replaceable hydrogen atoms attached to nitrogen maybe .preparedby knownmethods such as by the use of acyl, allrvl, aryl, or aralkyl halides or alkyl sulphates Besides using compounds of .the M ,type D-X.CsH-1SO2CI, various chemicallyequivalent processes may be. used instead, such as the. use of the anhydrides (p-X.C6I-I4SO2) 20 or thebro mides p-X.CsH4SO2Br.- H

The following examples illustrate .howthe in: vention may be carried out in practice', but it is to be understood that the invention is. in,no my limited to the details given in these examples:

Example 1 w 2-amino-pyridine (9.4 grams) is dissolved in.2 0 .cc. of, dry pyridine and'23.5 gramsof p-acetyl amino-benzene-sulphonyl chloride is added and the mixture heated on the steam bath. Water is then added and the precipitated.z-(p acetyk amino-benzene-sulphonamido) pyridine, M Pt. 224 C. hydrolysed by boiling with 1 '75 cc.'of 2N sodium hydroxide solution. The solution is cooled and made 'just acidto litmus by addition ofQ2N hydrochloric acid; The precipitate of 2-(pamino-benzene-sulphonamido)-pyridine is collected and recrystallised from water. Melting point 190? C. v

Example 2 To 16 grams of G-amino-quinaldine dissolved in 30 cc. of dry pyridine is addedZl grams of pacetylamino-,benzene-sulphonyl-chloride. After heating on a steam bath forl hour and diluting with water, the crystalline precipitate is collected, washed and purifiedby precipitation of the solution in normal sodium hydroxide solution with excess ofboiling 2N acetic acid, It melts at 272 C.

This is converted :to the amino compound by refluxing .for 30 minutes with ten times its weight of 2N sodium hydroxide solution. Onacidiflcation to Iitmusthe'fbase is obtained as a "sum to Congo red. The precipitated product is purified by solution in boiling alcohol and precipitation with water. Melting point 252 C.

Example 3 To a solution of 4.7 grams of 2-amino-pyridine in 10 cc. of dry pyridine is added, with cooling, 12 grammes of p-nitro-benzene-sulphonyl-chloride. An energetic reaction results: when this is over, the mixture is diluted with water, (200 cc.) and the precipitate of 2- (p-nitro-benzene-sulphonamido) -pyridine collected. Melting point 185' C.

v The nitro compound (1.4 grams) is dissolved in about cc. of 2N sodium hydroxide solution and the suspension of Na salt formed on standing is added at 20 C. to a paste of ferrous hydroxide from gramsferrous sulphate (hydrated) in 30 cc. waterand' 3 grams sodium hydroxide in 5 cc.

of water. After standing (1 hour) the mixture n is filtered from ferric hydroxide and the filtrate acidified with acetic acid. The 2- (p-amino-benzene-sulphonamido) -.pyridin'e melts at 190 C.

Example 4 16.5 grams of p-chlorobenzene sulphonylchloride is added to a solution of 7 grams of 2- amino-pyridine in 20 cc. of pyridine. After heating at 90 C. for minutes, water is added and the precipitated 2-(p-chlorobenzene-sulphonamido)-pyridine is collected, washed and dried, M. lt. 186 C. This is then heated in a closed vessel with 4 parts by weight of concentrated aqueous ammonia in the presence or about part by weight of cuprous chloride for 13 hours at 150-175 C.

The excess of ammonia is removed and on dilution with .water, 2-(p-amino benzene-sulphonamido) -pyridine is obtained and may be purified by crystallisation from water.

Example 5 amidol-pyridine, M. Pt. 224 is obtained from which 2 (p-amino-sulphonamido) is formed by alkaline hydrolysis.

Example 6 10 grams of p-nitro-benzene-sulphonic acid anhydride (prepared by the action of thionyl chloride on p-nitro-benzene-sulphonic acid dihydrate) are added to-a solution of 5 grams of 2-amino-pyridine in cc. of pyridine. The reaction mixture becomes warm and a precipitate pyridine .01? 2-(-p-nitro-benzene-sulphonamido) pyridine is formed. The. reaction mixture is diluted with water and dried. Melting point 195 C.

This compound onreduction according to the method of Example 3 yields 2-(p-amino-benzenesulphonamido) -pyridine.

Example 7 2.5- grams of 2-'(p-amino-benzene-sulphonamidial-pyridine is suspended in 10 cc. of pyridine at laboratory temperature and 2 grams p-nitrobenzoyl chloride is added. The mixture is allowed to cool, diluted with Water, and the precipitated 2 [p- (p -nitr0 benzoyl amino)-benzene sulphonamido] pyridine filtered o-fi, washed with water and dried. Melting point 272.

Example 8 5.4 grams of 5-amino-8-methoxy-quinoline is dissolved in 10 cc. of pyridine, 7.3 grams of p acetylamino-benzene-sulphonyl chloride added, and the mixture heated at C. for a short time. Water is then added and the precipitated 5-(pacetylamino benzene sulphonamido) 8- methoxy quinoline filtered ofi? and crystallised from dilute alcohol. Melting point 185 C.

On hydrolysis of this acetyl compound by boiling with 10 parts of 2N sodium hydroxide followed by neutralisation to Congo red, 5- (p-aminobenzene-sulphonamido) -8methoxy quinoline is obtained, which recrystallised from water, melts at 228-230 C. V

Example 9 6.6 grams of 2:6-diamino-pyridine is dissolved in 40 cc. of pyridine and 29.0 grams of p-acetyl amino-benzene-sulphonyl chloride added. When the reaction mixture has cooled, Water is added and the precipitated 2:6 di(p-acetylamino-benzene-sulphonamido) pyridine crystallised by so lution in boiling alcoholic sodium hydroxide and reprecipitation with hot acetic acid. Melting point 275 C. On hydrolysis by boiling for 1 hour with cc. of 2N caustic soda solution, and acidifying with dilute acetic acid 2:6 di(p-ami no-benzene-sulphonamido)-pyridine is precipitated. The crude product is purified by solution in boiling dilute sodium hydroxide and acidifying with dilute acetic acid, when the pure crystalline product, melting point 255 0., is obtained.

Example 10 5 grams of 2-hydroxy-4-methyl-7-amino-quinoline are suspended in 25 cc. of pyridine, 6.8 grams of p-acetylamino-benzene-sulphonyl chloride added, and the mixture heated on the Water bath for a short time. On dilution with water (100 cc.) the precipitated 2 hydroxyl-methyl- 7-(p-acetyl-amino-henzene-sulphonamido) quinoline is precipitated filtered off, Washed With water and crystallised from dilute alcohol. Melting point 304 C.

On hydrolysis of this compound by boiling for 1 hour with 10 parts of dilute caustic soda and subsequently acidifying with dilute acetic acid 2 hydroxy-4 methyl 7-(p-aminobenzene-sulphonamido) -quin0line is precipitated. After purification by solution in hot dilute sodium hydroxide and re-preaipitation by acidifying with hot acetic acid the pure compound melts at 289 C.

Example 11 14 grams of 2 amino-pyridine-3-carboxylic acid is suspended in 100 cc. of pyridine and 24 grams of p-acetylamino-benzene sulphonyl chloride added. The mixture is heated on the water bath for 10 minutes, diluted with water, and the precipitated 3 carboxy-Z-(p-acetylamino benzene-sulphonamido) pyridine recrystallised from alcohol. M. Pt. C. (dec.). On hydrolysis by boiling with 10 parts of dilute sodium hydroxide solution and acidifying with dilute acetic acid 3 carboxy-2-(p-aminobenzene-sulphonamido pyridine is precipitated, which is obtained crystalline by solution in hot dilute sodium hydroxide and acidification with acetic acid. Melting poin Example 12 Example 13 14 grams of G-amino-quinoline are dissolved in 30 cc. of quinoline and 24 grams of p-acetyla'mino-benzene-sulphonyl chloride added. mixture is heated on a steam bath for about 30 minutes and diluted with 300 cc. of water when B-(p-acetylamino-benzene sulphonamido) quinoline is precipitated, filtered off, washed with water and recrystallised. Melting point 275 C.

On hydrolysis with ten parts of boiling 2N caustic soda solution for 1 hour and acidifying with dilute acetic acid 6-(p-amino-benzene-sulphon-' amidol-quinoline is obtained. After crystallisation from dilute alcohol it melts at 200 C.

Example 14 4.7 grams of 2-amino pyridine are dissolved in 20 cc. of benzene, 12 grams of p-acetylaminobenzene-sulphonyl chloride added and the mixture allowed to stand. The solid which separates is filtered off and boiled for 1 hour with 90 cc. of 2N caustic soda solution. On acidification with dilute acetic acid 2-(p-amino-benzene sulphonamido) -pyridine is precipitated and recrystallised from acetone. Melting point 190 C.

Example 2 grams of 2-(p-chlor-benzene-sulphonamido) pyridine (Example 4) or 2 grams of Z-(p-brombenzene-sulphonamido) pyridine (obtained in a similar manner from p-brom -benzene-sulphonylchloride and 2 amino-pyridine) is heated in a closed vessel with 8 cc. of a 30 per cent. aqueous solution of methylamine, and 0.1 gram of cuprous chloride for 12 hours at 150 C. After cooling, the reaction mixture is diluted with water and the precipitated 2 (p-methyl-amino-benzenesulphonamido) pyridine purified by recrystallisation from alcohol. Melting point 154 C.

Example 16 9 grams of 2:4 dinitro-diphenylamino-4l-sulphonyl chloride prepared by the action of phosphorous pentachloride on the sodium salt of the corresponding sulphonic acid is added to a solution of 2.3 grams of Z-amino-pyridine in cc. of pyridine. When the reaction is complete, water is added and the precipitated 2-(p(2:4 dinitro-phenylamino) -benzene sulphonamido) pyridine filtered oil, washed, and crystallised from its solution in hot dilute alcoholic caustic soda by addition of 50 per cent. acetic acid. Melting point 230-233 C.

Example 17 5 grams of 2-(p-chlorbenzene-sulphonamido)- pyridine are heated in a closed vessel with 20 cc.

of a per cent. aqueous solution 'of dimethylamin and 0.25 gram of cuprous chloride at The 170 C. for 12 hours. After cooling, the contents of the tube are diluted with water and the precipitate extracted with cold dilute hydrochloric acid. Sodium acetate is then added to the acid extract and the precipitated 2-(p-dimethylaminobenzene sulphonamido)-pyridine recrystallised from alcohol. It melts at 2l8220 C.

. Example 18 15 grams of 4-amino-pyridine are dissolved in cc. of water, 40 grams of p-acetyl-amino-bem zene-sulphonyl chloride added followed by 10 grams of anhydrous'sodium carbonate. The mixture is stirred at room temperature for 1 hour and the precipitated 4-(p-acetylamino-benzene sulphonamido) -pyridine filtered off and washed with water. Crystallised from alcohol it melts at 252 C. Hydrolysis by boiling with 400 cc. of 2N caustic soda solution for 1 hour and acidifying the resulting solution with dilute acetic acid gives 4 p amino benzene sulphonamido) pyridine which on recrystallisation from dilute alcohol melts at 240 C.

Example 19 21.4 grams of p-acetylamino-benzene-sulphonamide, 13.5 grams of potassium carbonate, 1.0 grams of copper powder and 16.4 grams of 2- chloro-quinoline are heated together under reflux for 1% hours at 240-250 C. The cooled reaction mass is extracted with boiling water filtered and the filtrate acidified with acetic acid when crude 2-(p-acetylamino-benzene-sulphonamido) quinoline is precipitated.

O11 hydrolysis by boiling with 160 cc. of 2N sodium hydroxide for 1 hour and acidifying the resulting solution with acetic acid Z-(p-aminobenzene-sulphonamido) quinoline is obtained which after ire-solution in boiling dilute alkali and acidifying with hot acetic acid is obtained crystalline. Melting point 19'3-195 C.

Example 20 17 grams of 2-(p dimethylaminobenzene-sulphonamido)-pyridine (Example 1'7) is dissolved in 60 cc. of 2N sodium hydroxide solution, and '7 grams of dimethyl sulphate added with stirring to the cooled solution. 2-(p-dimethylamino-benzene-sulphonmethylamido) pyridine separates as an oil which rapidly solidifies and when recrystallised from dilute acetic acid melts at C.

Example 21 9.6 grams of 6 amino-quinaldine is dissolved in 27 cc. of pyridine and 11.8 grams of p-nitrobenzene-sulphonic-acid-anhydride added. .When the reaction is complete about 500 cc. of Water is added and the precipitated G-(p-nitro-benzene sulphonamido) quinaldine is filtered of!" and washed with water.

, On reduction with ferrous hydroxide as described in Exampl 3, 6-(-p-amino-benzene-sulphonamido) -quinaldine, melting point 252 C., is obtained.

Example 23 6.4 grams of. 2-amino-pyridine is dissolved in 50 cc. of pyridine and 22 grams of p-acetylbenzyl-amino-benzene-sulphonyl-chloride (British Patent 483,945) is added. When the reaction is complete the mixture is diluted with water and filtered, and the residual Z-(p-acetyl-benzylamino-benzene-sulphonamido) pyridine crystallised from alcohol. Melting point 177 C.

The acetyl compound on boiling with 30% sodium hydroxide solution for 12 hours and acidifying with acetic acid yields 2 (p-benzylaminobenzene-sulphonamido) pyridine which after recrystallisation from alcohol melts at 200.

' Example 24 9.7 grams of l-a-mino-isoquinoline is dissolved in cc. of pyridine and 16 grams of p-acetylamino-benzene-sulphonyl chloride added, the temperature being kept below 50 C. When the reaction is complete, water is added and the solid separated by filtration. After purification by dis- 12.5 grams of 2-(p-amino-benzene-sulphonamido) -pyridine is dissolved in cc. of 2N sodium hydroxide solutin and cc. of benzyl chloride gradually added with stirring. After standingfor 1 hour, 100 cc. of dry ether is added, and

the crude 2 (p-aminobenzene-sulphonbenzylamidobpyridine filtered off and extracted with 150 cc. of cold dilute hydrochloric acid. The residual 2 (p-amino-benzene-sulphonbenzyl amido) pyridine is filtered ofi and recrystallised irom alcohol. It melts at179 C.

Example 26 '7. grams of p-diethylamino-azobenzene-p-sulphonyl chloride (prepared by the action of phosphorus pentachloride on sodium p-diethylamino-azo-benzene sulphonate) is added to 1.9 grams of 2-amino-pyridine dissolved in 20 cc. of pyridine and after the reaction is over water is added. The precipitated 2-(p-diethyl-aminoazobenzene-p-sulphonamido).-pyridine is filtered ofi, washed with water, and dissolved in 5 parts of 2N sodium hydroxide solution. The solution is warmed to 30-40 C. and solid sodium hydrosulphite added gradually until the red colour of the solution is discharged. Acetic acid is then added until the solution is faintly acid; on concentration 2- (p-amino-benzene-sulphonamido) pyridine separates, and is purified by recrystallisation from alcohol. Melting point 190 C.

. Example 27 3 grams of p-acetyl-amino-benzene sulphonyl chloride are suspended in 5 cc. of chloroform and 1 gram of 2 amino-pyridine dissolved in 5 cc. of water is added. To the mixture is added 2 grams of anhydrous sodium carbonate and the whole vigorously shaken at room temperature for 1 hour. The mixture is diluted with 20 cc. of water, the chloroform layer together with any undissolved solid separated off and the chloroform removed, by distillation. The residue is .boiled with 25 cc. of 2N sodium hydroxide for 30 minutes and the solution precipitated by addition of hot glacial acetic acid until acid to litmus. The crystalline precipitate of 2-(pamino benzene sulphonamido) pyridine is filtered off and recrystallised from acetone. It melts at l89-190 C.

Example 28 A mixture of 4.6 grams of p-acetylaminobenzenesulphon methylamide, melting point 183 0., (obtained by the interaction of p-acetylaminobenzene-sulphonyl chloride and aqueous methylamine) 3.2 grams of 2-bromopyridine, 2.8 grams of potassium carbonate and 0.2 gram of copper powder is heated at 200 C. for 1 hour. The cooled melt is extracted with 50% acetic acid and the filtered extract is concentrated whereupon 2 (p-acetylamino-benzene-sulphon methylamidm-pyridine separates. Crystallised from dilute acetic acid, it melts at 231 C. Hydrolysis by boiling for 1 hour with 10 parts of 2N sodium hydroxide gives an acidification with acetic acid 2-(p-amino-benzene-sulphon-methylamido) -pyridine. Crystallised from alcohol it melts at 225 C.

Example 29 25 grams of phenyl-2-amino-pyridine-5-sul- Example 30 9.4 grams of 2 amino-pyridine is dissolved in cc. of acetone and 11.6 grams of p-acetylamino-benzenesulphonyl chloride is added. The

mixture is boiled under refiux for 1 hour, the,

acetone removed by distillation and the residue treated with water. The 2-(p-acetylaminobenzene sulphonamido)-pyridine so formed is collected. It melts at 224 C. when crystallised from aqueous alcohol.

Example 31 To 9.4 grams of 2-amino-pyridine at 55 C. is added 11.6 grams of p-acetylamino-benzene-sulphonyl chloride. When the reaction is over the melt is dissolved in cc. of 2N sodium hydroxide solution and the mixture is boiled under reflux for 1 hour. Acidification with acetic acid precipitates 2 (p-amino-benzene-sulphonamido) pyridine which melts at 190 C. when crystallised from aqueous alcohol.

Ewample 32 A mixture of 15.8 grams of 5-nitro-2-chloropyridine, 21.4 grams of p-acetylamino-benzene sulphonamide, 13.5 grams of potassium carbonate (anhydrous) and 1.0 grams of copper powder is heated for 30 minutes at C. The mixture is extracted with boiling water and filtered; acidification of the filtrate with acetic acid then gives 5 nitro 2-(p-acetylamino-benzene-sulphonamido)-pyridine. Melting point 264 C- Example 33 To a solution of 2.2 grams of -iodo-2-aminopyridine in 7 cc. of pyridine is added 2.4 grams of p acetylamino-benzene-sulphonyl chloride. When the reaction is over 70 cc. of water are added and the precipitate of 5-iodo-2-(p-acetylamino-benzene-su1phonamido) -pyridine is collected, washed with water and crystallised from 50% acetic acid. Melting point 234 C. Hydrolysis of this with parts of 2N sodium hydroxide solution by boiling for 1 hour under reflux followed by addition of excess of 2N acetic acid gives 5-iodo-2-(p-aminobenzene-sulphonamido) -pyridine. Purified by solution in boiling aqueous alcoholic sodium hydroxide followed by addition of boiling dilute acetic acid, it melts at 219 C.

Example 34 4.3 grams of 2-methylamino-pyridine is dissolved in 20 cc. of pyridine and 9.5 grams of pacetylamino benzene sulphonyl chloride is added. When the reaction mixture has cooled, 100 cc. of water are added and the precipitate of crude 2-(p acetylamino-benzene-sulphonmethylan1id0 -pyridine is collected, washed and crystallised from dilute acetic acid. Melting point 231 C.

Example 10 grams of 2-(p-aminobenzene-sulphonmethylamido) -pyridine (Example 21) is dissolved in cc. of 2N hydro-chloric acid and 10 cc. of acetic anhydride followed by suflicient saturated sodium acetate solution to remove Congo red acidity are added. The precipitate of 2 -(p acetylamino benzene-sulphonmethylamido) pyridine is collected, washed and crystallised from dilute acetic acid. Melting point 231 C.

What we claim and desire to secure by Letters Patent is:

The process for producing Z-(p-amino-benzene-sulphonamido) -quinoline which comprises reacting p-acetyl-amino-benzene-sulphonamide with 2-bromo-quinoline in the presence of potassium carbonate and copper powder for the production of 2 (p-acetylamino-benzene-sulphonamide)-quinoline, and hydrolysing the reaction product under alkaline conditions.

ARTHUR JAMES EWINS. MONTAGUE ALEXANDER PHILLIPS. 

